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Principal Investigator: William Nathaniel Brennen
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $394,398
Funding agency: National Cancer Institute
Though initially responsive to hormonal therapy, prostate cancer (PCa) invariably progresses to an incurable
metastatic castration-resistant state (mCRPC). Additionally, the proportion of patients with androgen receptor
(AR)-indifferent mCRPCe has increased significantly in the post-supracastration (e.g. -enzalutamide/-
abiraterone) era in men with late-stage lethal disease. Whether treatment-induced or otherwise, this emphasizes
the urgent need to develop innovative non-AR targeted approaches if we want to do more than provide
incremental increases in patient survival and combat this emerging highly-aggressive lethal phenotype. Tumor-
infiltrating fibroblast activation protein (FAP)-positive cells (i.e. MSCs, CAFs, and TAMs) are recognized as key
architects of the pro-tumorigenic and immunosuppressive microenvironment conducive to tumor progression.
This is in part through their production of energy-rich nutrients and metabolic intermediates that the cancer cells
“parasitize” from the extracellular fluid to fuel tumor growth and progression. These observations suggest that a
FAP-targeted therapy could provide an AR-independent multi-faceted anti-tumor assault by simultaneously
disrupting the parasitic dependence on the tumor stroma and eliminating multiple immunosuppressive cell types
within the tumor microenvironment (TME). To accomplish this goal, we have synthesized an orally-available
small molecule FAP-activated mitochondrial protoxin based on niclosamide, an FDA-approved anti-helminthic
that uncouples mitochondrial oxidative phosphorylation with nanomolar potency in a cell cycle-independent
manner, making it an ideal warhead for FAP+ stromal cells with a low proliferative index.
This proposal is innovative from conceptual and technical perspectives: 1) multiple tumor-infiltrating FAP+
cells in the TME are selectively and simultaneously targeted to overcome the immune barrier and disrupt the
“parasitic cycle” fueling tumor growth; 2) a first-in-class enzymatically-activated lipophilic mitochondrial protoxin
designed to increase the therapeutic index of an FDA-approved drug while sparing toxicity to surrounding healthy
tissue is synthesized and characterized; 3) FAP expression patterns in a unique series of human prostate tissues,
lymph nodes, and metastases as a function of malignancy and treatment status are assessed to identify clinical
states most likely to benefit from FAP-targeted therapy; and 4) efficacy, toxicity, and specificity are evaluated
using a novel series of patient-derived xenograft (PDX) and syngeneic models that recapitulate key clinical
features of human PCa in order to delineate biologically-relevant immune-independent and –dependent
mechanisms underlying the anti-tumor response. Furthermore, this strategy combines agents that have been
individually tested in patients, which significantly bolsters potential for near-term patient benefit. More
immediately, the proposal will provide important insights into the role of FAP+ cells in PCa pathophysiology
particularly with respect to their interaction with the immune system, while providing the necessary preclinical
proof-of-principle data needed to translate this innovative therapeutic platform into the clinic.
Terms: <Androgen Receptor><Androgenic Agents><Androgenic Compounds><Androgens><Anthelmintics><Antihelminthic Agent><Antihelminthic Drugs><Antitumor Response><Binding><Biologic Models><Biological Models><Body Tissues><CRISPR><CRISPR/Cas system><Cancer Patient><Cancers><Carcinoma><Castration><Cell Body><Cell Cycle><Cell Division Cycle><Cell-Mediated Lympholytic Cells><Cells><Classification><Clinic><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Data><Dependence><Disease><Disease Progression><Disorder><Distant Cancer><Distant Metastasis><Drug Kinetics><Drugs><Dysfunction><Embryo><Embryonic><Endocrine Therapy><Epithelial cancer><Esteroproteases><Extracellular Fluid><FDA approved><Fibroblasts><Functional disorder><Future><GEM model><GEMM model><Generalized Growth><Genetically Engineered Mouse><Goals><Growth><Heterograft><Heterologous Transplantation><Hormonal><Hormonal Therapy><Human><Immune><Immune Surveillance><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunologic Surveillance><Immunologic Surveillances><Immunological><Immunological Surveillance><Immunological Surveillances><Immunologically><Immunologics><Immunosurveillance><In Vitro><Individual><Infiltration><KO mice><Knock-out Mice><Knockout Mice><Laboratories><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Malignant Cell><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Medication><Membrane><Mesenchymal Progenitor Cell><Mesenchymal Stem Cells><Mesenchymal progenitor><Mesenchymal stromal/stem cells><Metabolic><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Prostate Cancer><Metastatic Tumor><Mice><Mice Mammals><Mitochondria><Model System><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Myeloid-derived suppressor cells><Neoplasm Metastasis><Neuroendocrine><Neuroendocrine System><Neurosecretory Systems><Normal Tissue><Normal tissue morphology><Null Mouse><Nutrient><Oral><Outcome><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><PDX model><Parasites><Patient derived xenograft><Patients><Pattern><Pelvic Lymph Node><Pelvic lymph node group><Peptidases><Peptide Hydrolases><Pharmaceutical Preparations><Pharmacokinetics><Phenotype><Physiopathology><Population><Pre-Clinical Model><Preclinical Models><Production><Property><Prostate><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate Carcinoma Metastatic><Prostate Gland><Prostate malignancy><Prostatic Cancer><Prostatic Gland><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><Reporting><Research Specimen><Resistance><Role><Secondary Neoplasm><Secondary Tumor><Series><Specificity><Specimen><Stromal Cells><Stromal Neoplasm><Stromal Tumor><Surface><Surgical Castration><Systematics><T cell infiltration><Testing><Therapeutic><Therapeutic Androgen><Therapeutic Index><Time><Tissue Growth><Tissues><Toxic effect><Toxicities><Transgenic Model><Transgenic Organisms><Translating><Translations><Tumor-associated macrophages><Vermifuges><Xenograft><Xenograft procedure><Xenotransplantation><Xtandi><abiraterone><advanced disease><advanced illness><anti-tumor immune response><anti-tumor response><antihelminthic><assault><assess effectiveness><cancer cell><cancer metastasis><cancer microenvironment><cancer progression><cell type><check point blockade><checkpoint blockade><clinical relevance><clinically relevant><combat><design><designing><determine effectiveness><determine efficacy><drug/agent><effectiveness assessment><effectiveness evaluation><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><enzalutamide><epithelial carcinoma><evaluate effectiveness><evaluate efficacy><examine effectiveness><examine efficacy><experiment><experimental research><experimental study><experiments><extracellular><fibroblast activating factor><fibroblast activation protein><fibroblast proliferation factor><fibroblast-activating factor><genetically engineered mouse model><genetically engineered murine model><hormone therapy><immune check point blockade><immune checkpoint blockade><immune microenvironment><immunosuppressive microenvironment><immunosuppressive myeloid cells><immunosuppressive tumor microenvironment><in vivo><indexing><innovate><innovation><innovative><insight><killer T cell><lipophilicity><lymph gland><lymph nodes><lymphnodes><malignancy><membrane structure><men><mesenchymal stromal progenitor cells><mesenchymal-derived stem cells><mitochondrial><myeloid suppressor cells><myeloid-derived suppressive cells><nano-molar><nanomolar><neoplasm progression><neoplasm/cancer><neoplastic progression><novel><ontogeny><pathophysiology><patient derived xenograft model><patient population><permissiveness><pre-clinical><preclinical><prostate cancer progression><prostate cancer treatment><protein expression><recruit><resistance mechanism><resistant><resistant mechanism><response><small molecule><social role><suppressive myeloid cells><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transgenic><transgenic trait><translation><tumor><tumor cell metastasis><tumor growth><tumor immune microenvironment><tumor microenvironment><tumor progression><tumor-immune system interactions><tumorigenic><xeno-transplant><xeno-transplantation>